Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy

Abstract

DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The ‘Y-family’ trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate damaged genomes, thereby conferring DNA damage tolerance. Moreover, Y-family DNA polymerases are inherently error-prone and cause mutations. Therefore, TLS DNA polymerases are potential mediators of important tumorigenic phenotypes. The skin cancer-propensity syndrome xeroderma pigmentosum-variant (XPV) results from defects in the Y-family DNA Polymerase Pol eta (Polη) and compensatory deployment of alternative inappropriate DNA polymerases. However, the extent to which dysregulated TLS contributes to the underlying etiology of other human cancers is unclear. Here we consider the broad impact of TLS polymerases on tumorigenesis and cancer therapy. We survey the ways in which TLS DNA polymerases are pathologically altered in cancer. We summarize evidence that TLS polymerases shape cancer genomes, and review studies implicating dysregulated TLS as a driver of carcinogenesis. Because many cancer treatment regimens comprise DNA-damaging agents, pharmacological inhibition of TLS is an attractive strategy for sensitizing tumors to genotoxic therapies. Therefore, we discuss the pharmacological tractability of the TLS pathway and summarize recent progress on development of TLS inhibitors for therapeutic purposes.

APOBEC3A induces DNA gaps through PRIMPOL and confers gap-associated therapeutic vulnerability

“…TLS is a DDT pathway that allows replication forks to bypass certain types of DNA lesions. Notably, TLS was recently shown to repair ssDNA gaps in BRCA1/2-deficient cells ( 17 , 35 ). Furthermore, an A3A-induced mutation signature in cancer cells is dependent on REV1, a key player in TLS ( 6 ).…”

The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities

“…DDR TransSigGroup 2 and TransSigGroup 5 also contain genes encoding the S-phase Checkpoint kinase CHEK1 and its activators TOPBP1 and RAD1 ( 43 ). Genes encoding other important mediators of DNA replication fork progression are also present in DDR TransSigGroup 2 and TransSigGroup 5 including the Trans-Lesion Synthesis (TLS) factors RAD18 and POLH, and the Template Switch (TS) factor HLTF which cooperates with RAD18 ( 44 ). In DDR TransSigGroup 5 and TransSigGroup 2 gene lists there is very strong representation of mRNAs encoding mediators of the Fanconi Anemia FA) and Homologous Recombination (HR) pathways (Table 1 ) which also facilitate replication fork progression in times of stress.…”

The DNA Damage Response (DDR) landscape of endometrial cancer defines discrete disease subtypes and reveals therapeutic opportunities

“…TransSigGroup2 and 5 also contain genes encoding the S-phase Checkpoint kinase CHEK1 and its activators TOPBP1 and RAD1 39 . Genes encoding other important mediators of DNA replication fork progression are also present in TransSigGroup2 and 5 including the Trans-Lesion Synthesis (TLS) factors RAD18 and POLH, and the Template Switch (TS) factor HLTF (which cooperates with RAD18) 40 . In TransSigGroup5 and 2 gene lists there is very strong representation of mRNAs encoding mediators of the Fanconi Anemia FA) and Homologous Recombination (HR) pathways (Table 1) which also facilitate replication fork progression in times of stress.…”

“…Oncogene-induced DNA replication stress represents a major source of intrinsic DNA damage in cancer cells. 11,17,40,[43][44][45] Diverse mechanisms have been proposed to explain how oncogenes induce DNA replication stress (including re-replication, hyper-transcription and R-loop collisions, reactive oxygen species, and altered replication licensing). Moreover, different oncogenes may induce different species of DNA damage.…”